Kappa agonist compounds and pharmaceutical formulations thereof

- Adolor Corporation

Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.The compound of formula II has the structure: ##STR1## wherein X.sub.4, X.sub.5 ;R.sub.1, R.sub.2 ; andAr and n are as described in the specification.

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Claims

1. A compound of the formula II or a pharmaceutically acceptable salt thereof ##STR154## wherein n=1-3;

R.sub.1 and R.sub.2 are independently.dbd.CH.sub.3; --(CH.sub.2).sub.m, where m=4-8, --CH.sub.2 CH(OH)(CH.sub.2).sub.2 --; --CH.sub.2 CH(F)(CH.sub.2).sub.2 --;
--(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --; or --(CH.sub.2).sub.2 CH.dbd.CHCH.sub.2 --;
Ar=unsubstituted or mono-, or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH.sub.3, SO.sub.2 CH.sub.3, CF.sub.3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X.sub.4 and X.sub.5 are independently
--Op(O)(OBn).sub.2; --OP(O)(OH),; --CO.sub.2 H; --SO.sub.3 H; --SO.sub.3 H; --O(CH.sub.2).sub.n CO.sub.2 H;
--NHSO.sub.2 CH.sub.3; --CONH(CH.sub.2).sub.s CO.sub.2 H; or --SO.sub.2 NH(CH.sub.2).sub.s CO.sub.2 H; wherein s=1-5
R.sub.5 =--H or --Ac
X.sub.6 =--CO.sub.2 H; --NHSO.sub.2 CH.sub.3; --NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or --OP(O)(OH).sub.2.

4. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising a compound of claim 2 in a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a compound of claim 3 in a pharmaceutically acceptable carrier.

7. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of claim 1.

8. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of claim 2.

9. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound of claim 3.

10. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of claim 4.

11. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of claim 5.

12. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of the pharmaceutical composition of claim 6.

13. A pharmaceutical composition comprising a compound of claim 1 and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound of claim 2 and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a compound of claim 3 and an antibiotic, antiviral, antifungal, anti-inflammatory agent or a mixture thereof in a pharmaceutically acceptable carrier.

Referenced Cited
U.S. Patent Documents
4065573 December 27, 1977 Lednicer
4098904 July 4, 1978 Szmuszkovicz
4145435 March 20, 1979 Szmuszkovicz
4212878 July 15, 1980 Lednicer et al.
4359476 November 16, 1982 Kaplan et al.
4438130 March 20, 1984 Kaplan
4663343 May 5, 1987 Horwell et al.
4855316 August 8, 1989 Horwell et al.
4906655 March 6, 1990 Horwell et al.
Foreign Patent Documents
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WO 92/20657 November 1992 WOX
Other references
  • McMahon et al., TINS, vol. 15, No. 12 (1992). Bernstein et al., Journal of Investigative Dermatology, 78: 82-83 (1982). Ballantyne et al., Pain, 33: 149-160 (1988). J. D. Bernhard, J. Am. Acad. Derm. 24: 309 (1991). IASP Newsletter, Sep./Oct. 1996. Thomas et al., Brain Research, 695: 267-270 (1995). CA 115: 8474w Naphto and benzo . . . benzeneacetamide. Freeman et al., p. 827. 1991. CA 120: 544309e DuP 747: structure activity relationship study. Rajagopalan et al.p. 968. 1994.
Patent History
Patent number: 5744458
Type: Grant
Filed: Jul 23, 1997
Date of Patent: Apr 28, 1998
Assignee: Adolor Corporation (Malvern, PA)
Inventors: Lawrence I. Kruse (Haddonfield, NJ), An-Chih Chang (Phoenixville, PA), Diane L. DeHaven-Hudkins (Chester Springs, PA), John J. Farrar (Chester Springs, PA), Forrest Gaul (Glen Moore, PA), Virendra Kumar (Paoli, PA), Michael Anthony Marella (Exton, PA), Alan L. Maycock (Malvern, PA), Wei Yuan Zhang (Collegeville, PA)
Primary Examiner: Joseph McKane
Attorney: Imre Balogh
Application Number: 8/899,086